Enteroviruses (EVs) are ubiquitous viruses which pose a significant risk to human pregnancies. In utero infections may lead to maternal illness; neonatal illnesses, including meningoencephalitis, myocarditis, hepatitis, and/or sepsis; premature delivery; fetal myocarditis and death; fetal hepatic and adrenal necrosis and demise; and congenital malformations of the cardiovascular, gastrointestinal, genitourinary, and central nervous systems. The pathogenesis of these gestational infections is poorly understood. The proposed project will investigate the significance of transplacental EV infection, the mechanisms employed by the placenta to protect against fetal infection, and factors which may cause those mechanisms to break down. The effects of intrauterine EV infection on the placenta and fetus will be elucidated, and factors influencing fetal outcome will be delineated. Immunologic and pharmacologic strategies to prevent fetal morbidity associated with EV infections will be evaluated. Studies will be performed in a murine model of gestational EV infection which utilizes a natural EV of mice, Theiler's murine encephalomyelitis virus (TMEV). In this model, placentas and fetuses are readily infected following maternal inoculation with TMEV in early gestation, while in late gestation, placentas are infected but the fetus is never infected. Experiments will be performed in this model to determine whether the evolution of this placental barrier to viral transmission is based on anatomic and structural features (examining placentas containing virus and placentas containing inert particles of similar size by electron microscopy), immunologic phenomena (studying infected placentas with immunohistochemistry and studying viral infection of distinct placental cell populations in vitro), and/or changes in placental cell susceptibility to viral infection (employing placental cell culture techniques). Morphologic studies, tissue culture, in situ hybridization, and immunohistochemistry will be used to elucidate the effects of TMEV infection on the placenta and the fetus. Host and viral factors which may affect the rate of transplacental infection and/or the outcome of fetal infection will be assessed by varying maternal physiologic parameters (age, physical stress, nutrition, uteroplacental blood flow) and by studying viral mutants in this model. Finally, immunologic and pharmacologic strategies to prevent transplacental infection and/or prevent adverse outcome of fetal infection will be tested in this animal model. These studies will shed light on protective mechanisms employed by the human placenta, effects of EVs on human fetuses, and possible treatment strategies for human pregnancies at risk. The results will have relevance not only for EV infections, but also for infections by other viruses which threaten the human fetus.